tbuckley/cabot-search huggingface dataset:
Integrative Omics Reveals Rapidly Evolving Regulatory Sequences Driving Primate Brain Evolution
Authors: Xiao-Lin Zhuang, Jin-Jin Zhang, Yong Shao, Yaxin Ye, Chun-Yan Chen, Long Zhou, Zheng-bo Wang, Xin Luo, Bing Su, Yong-Gang Yao, David N Cooper, Ben-Xia Hu, Lu Wang, Xiao-Guang Qi, Jiangwei Lin, Guo-Jie Zhang, Wen Wang, Nengyin Sheng, Dong-Dong Wu
Journal: Molecular Biology and Evolution (2023)

Abstract Although the continual expansion of the brain during primate evolution accounts for our enhanced cognitive capabilities, the drivers of brain evolution have scarcely been explored in these ancestral nodes. Here, we performed large-scale comparative genomic, transcriptomic, and epigenomic analyses to investigate the evolutionary alterations acquired by brain genes and provide comprehensive listings of innovatory genetic elements along the evolutionary path from ancestral primates to human. The regulatory sequences associated with brain-expressed genes experienced rapid change, particularly in the ancestor of the Simiiformes. Extensive comparisons of single-cell and bulk transcriptomic data between primate and nonprimate brains revealed that these regulatory sequences may drive the high expression of certain genes in primate brains. Employing in utero electroporation into mouse embryonic cortex, we show that the primate-specific brain-biased gene BMP7 was recruited, probably in the ancestor of the Simiiformes, to regulate neuronal proliferation in the primate ventricular zone. Our study provides a comprehensive listing of genes and regulatory changes along the brain evolution lineage of ancestral primates leading to human. These data should be invaluable for future functional studies that will deepen our understanding not only of the genetic basis of human brain evolution but also of inherited disease.
Third-Generation Sequencing Reveals the Adaptive Role of the Epigenome in Three Deep-Sea Polychaetes
Authors: Maeva Perez, Oluchi Aroh, Yanan Sun, Yi Lan, Stanley Kim Juniper, Curtis Robert Young, Bernard Angers, Pei-Yuan Qian
Journal: Molecular Biology and Evolution (2023)

The roles of DNA methylation in invertebrates are poorly characterized, and critical data are missing for the phylum Annelida. We fill this knowledge gap by conducting the first genome-wide survey of DNA methylation in the deep-sea polychaetes dominant in deep-sea vents and seeps: Paraescarpia echinospica, Ridgeia piscesae, and Paralvinella palmiformis. DNA methylation calls were inferred from Oxford Nanopore sequencing after assembling high-quality genomes of these animals. The genomes of these worms encode all the key enzymes of the DNA methylation metabolism and possess a mosaic methylome similar to that of other invertebrates. Transcriptomic data of these polychaetes support the hypotheses that gene body methylation strengthens the expression of housekeeping genes and that promoter methylation acts as a silencing mechanism but not the hypothesis that DNA methylation suppresses the activity of transposable elements. The conserved epigenetic profiles of genes responsible for maintaining homeostasis under extreme hydrostatic pressure suggest DNA methylation plays an important adaptive role in these worms.
Dopamine release and negative valence gated by inhibitory neurons in the laterodorsal tegmental nucleus
Authors: Yonglan Du, Siyao Zhou, Chenyan Ma, Hui Chen, Ana Du, Guochuang Deng, Yige Liu, Amanda J. Tose, Li Sun, Yijun Liu, Hangjun Wu, Huifang Lou, Yan-qin Yu, Ting Zhao, Stephan Lammel, Shumin Duan, Hongbin Yang
Journal: Neuron (2023)
Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis
Authors: Máté G. Kiss, Nikolina Papac-Miličević, Florentina Porsch, Dimitrios Tsiantoulas, Tim Hendrikx, Minoru Takaoka, Huy Q. Dinh, Marie-Sophie Narzt, Laura Göderle, Mária Ozsvár-Kozma, Michael Schuster, Nikolaus Fortelny, Anastasiya Hladik, Sylvia Knapp, Florian Gruber, Matthew C. Pickering, Christoph Bock, Filip K. Swirski, Klaus Ley, Alma Zernecke, Clément Cochain, Claudia Kemper, Ziad Mallat, Christoph J. Binder
Journal: Immunity (2023)
Maturation of iPSC-derived cardiomyocytes in a heart-on-a-chip device enables modeling of dilated cardiomyopathy caused by R222Q-SCN5A mutation
Authors: Marianne Wauchop, Naimeh Rafatian, Yimu Zhao, Wenliang Chen, Mark Gagliardi, Stéphane Massé, Brian J. Cox, Patrick Lai, Timothy Liang, Shira Landau, Stephanie Protze, Xiao Dong Gao, Erika Yan Wang, Kelvin Chan Tung, Zachary Laksman, Rick Xing Ze Lu, Gordon Keller, Kumaraswamy Nanthakumar, Milica Radisic, Peter H. Backx
Journal: Biomaterials (2023)
Senescence‐based colorectal cancer subtyping reveals distinct molecular characteristics and therapeutic strategies
Authors: Min‐Yi Lv, Du Cai, Cheng‐Hang Li, Junguo Chen, Guanman Li, Chuling Hu, Baowen Gai, Jiaxin Lei, Ping Lan, Xiaojian Wu, Xiaosheng He, Feng Gao
Journal: MedComm (2023)

Cellular senescence has been listed as a hallmark of cancer, but its role in colorectal cancer (CRC) remains unclear. We comprehensively evaluated the transcriptome, genome, digital pathology, and clinical data from multiple datasets of CRC patients and proposed a novel senescence subtype for CRC. Multi-omics data was used to analyze the biological features, tumor microenvironment, and mutation landscape of senescence subtypes, as well as drug sensitivity and immunotherapy response. The senescence score was constructed to better quantify senescence in each patient for clinical use. Unsupervised learning revealed three transcriptome-based senescence subtypes. Cluster 1, characterized by low senescence and activated proliferative pathways, was sensitive to chemotherapeutic drugs. Cluster 2, characterized by intermediate senescence and high immune infiltration, exhibited significant immunotherapeutic advantages. Cluster 3, characterized by high senescence, high immune, and stroma infiltration, had a worse prognosis and maybe benefit from targeted therapy. We further constructed a senescence scoring system based on seven senescent genes through machine learning. Lower senescence scores were highly predictive of longer disease-free survival, and patients with low senescence scores may benefit from immunotherapy. We proposed the senescence subtypes of CRC and our findings provide potential treatment interventions for each CRC senescence subtype to promote precision treatment.
Carfilzomib-induced thrombotic microangiopathy (TMA): an under-recognised spectrum of disease from microangiopathic haemolysis to subclinical TMA
Authors: Royston Ponraj, Adam Bryant, Lindsay Dunlop, Heather Range, Cherry Cobrador, Silvia Ling, Danny Hsu
Journal: Blood Cancer Journal (2023)

Carfilzomib-induced thrombotic microangiopathy (TMA): an under-recognised
ISLET: individual-specific reference panel recovery improves cell-type-specific inference
Authors: Hao Feng, Guanqun Meng, Tong Lin, Hemang Parikh, Yue Pan, Ziyi Li, Jeffrey Krischer, Qian Li
Journal: Genome biology (2023)

Abstract We propose a statistical framework ISLET to infer individual-specific and cell-type-specific transcriptome reference panels. ISLET models the repeatedly measured bulk gene expression data, to optimize the usage of shared information within each subject. ISLET is the first available method to achieve individual-specific reference estimation in repeated samples. Using simulation studies, we show outstanding performance of ISLET in the reference estimation and downstream cell-type-specific differentially expressed genes testing. We apply ISLET to longitudinal transcriptomes profiled from blood samples in a large observational study of young children and confirm the cell-type-specific gene signatures for pancreatic islet autoantibody. ISLET is available at https://bioconductor.org/packages/ISLET .
Clinical evidence of human pathogens implicated in Alzheimer’s disease pathology and the therapeutic efficacy of antimicrobials: an overview
Authors: Celso S. G. Catumbela, Vijayasree V. Giridharan, Tatiana Barichello, Rodrigo Morales
Journal: Translational Neurodegeneration (2023)

A wealth of pre-clinical reports and data derived from human subjects and brain autopsies suggest that microbial infections are relevant to Alzheimer's disease (AD). This has inspired the hypothesis that microbial infections increase the risk or even trigger the onset of AD. Multiple models have been developed to explain the increase in pathogenic microbes in AD patients. Although this hypothesis is well accepted in the field, it is not yet clear whether microbial neuroinvasion is a cause of AD or a consequence of the pathological changes experienced by the demented brain. Along the same line, the gut microbiome has also been proposed as a modulator of AD. In this review, we focus on human-based evidence demonstrating the elevated abundance of microbes and microbe-derived molecules in AD hosts as well as their interactions with AD hallmarks. Further, the direct-purpose and potential off-target effects underpinning the efficacy of anti-microbial treatments in AD are also addressed.
Phosphatidylserine decarboxylase downregulation in uric acid‑induced hepatic mitochondrial dysfunction and apoptosis
Authors: Ning Liu, Lei Huang, Hu Xu, Xinyu He, Xueqing He, Jun Cao, Wenjun Xu, Yaoxing Wang, Hongquan Wei, Sheng Wang, Hong Zheng, Shan Gao, Youzhi Xu, Wenjie Lu
Journal: MedComm (2023)

The molecular mechanisms underlying uric acid (UA)-induced mitochondrial dysfunction and apoptosis have not yet been elucidated. Herein, we investigated underlying mechanisms of UA in the development of mitochondrial dysfunction and apoptosis. We analyzed blood samples of individuals with normal UA levels and patients with hyperuricemia. Results showed that patients with hyperuricemia had significantly elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, which may indicate liver or mitochondrial damage in patients with hyperuricemia. Subsequently, lipidomic analysis of mouse liver tissue mitochondria and human liver L02 cell mitochondria was performed. Compared with control group levels, high UA increased mitochondrial phosphatidylserine (PS) and decreased mitochondrial phosphatidylethanolamine (PE) levels, whereas the expression of mitochondrial phosphatidylserine decarboxylase (PISD) that mediates PS and PE conversion was downregulated. High UA levels also inhibited signal transducer and activator of transcription 3 （STAT3） phosphorylation as well as mitochondrial respiration, while inducing apoptosis both in vivo and in vitro. Treatment with allopurinol, overexpression of PISD, and lyso-PE (LPE) administration significantly attenuated the three above-described effects in vitro. In conclusion, UA may induce mitochondrial dysfunction and apoptosis through mitochondrial PISD downregulation. This study provides a new perspective on liver damage caused by hyperuricemia.
Innovative stem cell-based strategies for corneal wound healing: A step forward
Authors: Sharmila Fagoonee, Gabriele Saccu, Benedetta Bussolati
Journal: Molecular Therapy (2023)

Corneal damage caused by chemical agents is a frequent occupational hazard and is responsible for 11%–22% of ocular traumas. 1 Sharma N. Kaur M. Agarwal T. Sangwan V.S. Vajpayee R.B. Treatment of acute ocular chemical burns. Surv. Ophthalmol. 2018; 63: 214-235https://doi.org/10.1016/j.survophthal.2017.09.005 Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar It requires prompt intervention to avoid serious scarring and vision loss. On top of existing medical therapy and surgical treatment, regenerative medicine has provided novel therapeutic possibilities for corneal injuries. 2 Saccu G. Menchise V. Giordano C. Delli Castelli D. Dastrù W. Pellicano R. Tolosano E. Van Pham P. Altruda F. Fagoonee S. Regenerative Approaches and Future Trends for the Treatment of Corneal Burn Injuries. J. Clin. Med. 2021; 10: 317https://doi.org/10.3390/jcm10020317 Crossref PubMed Scopus (9) Google Scholar However, the corneal epithelium is a heterogeneous tissue structured in five highly organized layers (corneal epithelium, Bowman's layer, corneal stroma, Descemet's membrane, and corneal endothelium) with multiple cell types. Thus, to orchestrate its regeneration, the coordinated action of numerous signaling pathways, a specific microenvironment and special extracellular matrix components are required. Finding strategies for efficient corneal replacement has become essential (Figure 1).
Author Correction: Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible
Authors: Anubhuti Goel, Daniel A Cantu, Janna Guilfoyle, Gunvant R Chaudhari, Aditi Newadkar, Barbara Todisco, Diego de Alba, Nazim Kourdougli, Lauren M Schmitt, Ernest Pedapati, Craig A Erickson, Carlos Portera-Cailliau
Journal: Nature Neuroscience (2023)
Case 23-2023: A 21-Year-Old Man with Progressive Dyspnea
Authors: Bradley A. Maron, Alison S. Witkin, David M. Dudzinski, Anuradha S. Shenoy-Bhangle, Wei Zhang, Stuti G. Shroff
Journal: New England Journal of Medicine (2023)

A 21-year-old man was evaluated because of progressive dyspnea. A frontal chest radiograph showed enlarged hila and an irregular calcification in the liver. A diagnosis was made.
Double Balloon Enteroscopy Guided Band Ligation and Auto-Amputation for Treatment of a Large Hemorrhagic Lymphangioma
Authors: Rachel Hannum, Asif Khalid, Charles Gabbert
Journal: Clinical Gastroenterology and Hepatology (2023)

A 65-year-old woman with history of Roux-en-Y gastric bypass presented with iron deficiency anemia. Initial evaluation with esophagogastroduodenoscopy and colonoscopy was unrevealing, thus video capsule endoscopy was performed. Fresh hematin was noted at 3 hours 30 minutes, with an overall small bowel transit time of 5 hours 45 minutes. Subsequent anterograde double balloon enteroscopy revealed an actively oozing, >5-cm lobular lesion extending over several folds in the proximal ileum (Figure A). Argon plasma coagulation was applied for hemostasis and the margin tattooed. Biopsies were consistent with a hemorrhagic lymphangioma and prominent peripheral lymphangiectasia. In view of benign etiology and uncertain lesion depth, we proceeded with band ligation and autoamputation. The Speedband Superview Super 7 System (Boston Scientific) cap diameter was determined to be compatible with the enteroscope (FUJIFILM, EN-580T) diameter and balloon (Figure B). The 110-cm banding cable was detached and the "hub end" was attached to the opposite end on a second system using a loop-within-loop pull method (Supplementary image). The cap was then connected to the elongated cable, providing the necessary 200-cm length required for the enteroscope and allowing for multiband ligation. Five bands were deployed over the expansive lesion without complication (Figure C). Follow-up revealed complete eradication of the hemorrhagic lymphangioma and resolution of anemia (Figure D). This case demonstrates compatibility of standard multiband devices with an enteroscope using a simple method to elongate the cable, and a potential role for band ligation and autoamputation in the management of bleeding lesions deep in the small bowel.
Bidirectional Mendelian Randomization and Multiphenotype GWAS Show Causality and Shared Pathophysiology Between Depression and Type 2 Diabetes
Authors: Jared G. Maina, Zhanna Balkhiyarova, Arie Nouwen, Igor Pupko, Anna Ulrich, Mathilde Boissel, Amélie Bonnefond, Philippe Froguel, Amna Khamis, Inga Prokopenko, Marika Kaakinen
Journal: Diabetes Care (2023)

Depression is a common comorbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them.We applied two-sample, bidirectional Mendelian randomization (MR) to assess causality between type 2 diabetes and depression. We investigated potential mediation using two-step MR. To identify shared genetics, we performed 1) genome-wide association studies (GWAS) separately and 2) multiphenotype GWAS (MP-GWAS) of type 2 diabetes (19,344 case subjects, 463,641 control subjects) and depression using major depressive disorder (MDD) (5,262 case subjects, 86,275 control subjects) and self-reported depressive symptoms (n = 153,079) in the UK Biobank. We analyzed expression quantitative trait locus (eQTL) data from public databases to identify target genes in relevant tissues.MR demonstrated a significant causal effect of depression on type 2 diabetes (odds ratio 1.26 [95% CI 1.11-1.44], P = 5.46 × 10-4) but not in the reverse direction. Mediation analysis indicated that 36.5% (12.4-57.6%, P = 0.0499) of the effect from depression on type 2 diabetes was mediated by BMI. GWAS of type 2 diabetes and depressive symptoms did not identify shared loci. MP-GWAS identified seven shared loci mapped to TCF7L2, CDKAL1, IGF2BP2, SPRY2, CCND2-AS1, IRS1, CDKN2B-AS1. MDD has not brought any significant association in either GWAS or MP-GWAS. Most MP-GWAS loci had an eQTL, including single nucleotide polymorphisms implicating the cell cycle gene CCND2 in pancreatic islets and brain and the insulin signaling gene IRS1 in adipose tissue, suggesting a multitissue and pleiotropic underlying mechanism.Our results highlight the importance to prevent type 2 diabetes at the onset of depressive symptoms and the need to maintain a healthy weight in the context of its effect on depression and type 2 diabetes comorbidity.
Clinical outcome of Mantle Cell Lymphoma patients with high-risk disease (high-risk MIPI-c or high p53 expression)
Authors: Gabriel Scheubeck, Linmiao Jiang, Olivier Hermine, Hanneke C. Kluin-Nelemans, Christian Schmidt, Michael Unterhalt, Andreas Rosenwald, Wolfram Klapper, Andrea Evangelista, Marco Ladetto, Mats Jerkeman, Simone Ferrero, Martin Dreyling, Eva Hoster
Journal: Leukemia (2023)

Currently, treatment allocation of patients with Mantle Cell Lymphoma (MCL) is mainly based on age and medical fitness. The combined MCL International Prognostic Index (MIPI-c) allows to predict prognosis using clinical factors (MIPI) and the Ki-67 index. However, high p53 expression as surrogate for TP53 alterations has demonstrated to be an independent predictor for poor outcome. We aimed to define a clear high-risk group based on the combination of MIPI, Ki-67 and p53 expression/TP53 alteration. A total of 684 patients from the prospective European MCL-Younger and MCL-Elderly trials were evaluable. The classification of high-risk disease (HRD) as high-risk MIPI-c or p53 expression >50% versus low-risk disease (LRD) as low, low-intermediate or high-intermediate MIPI-c and p53 expression ≤50% allowed to characterize two distinct groups with highly divergent outcome. Patients with HRD had significantly shorter median failure-free survival (FFS) (1.1 vs. 5.6 years, p < 0.0001) and overall survival (OS) (2.2 vs. 13.2 years, p < 0.0001) compared to those with LRD. These major differences were confirmed in two validation cohorts from the Italian MCL0208 and the Nordic-MCL4 trials. The results suggest that this subset of HRD patients is not sufficiently managed with the current standard treatment and is asking for novel treatment strategies.
Unraveling Prevalence and Effects of Deleterious Mutations in Maize Elite Lines across Decades of Modern Breeding
Authors: Shichao Sun, Baobao Wang, Changyu Li, Gen Xu, Jinliang Yang, Matthew B Hufford, Jeffrey Ross-Ibarra, Haiyang Wang, Li Wang
Journal: Molecular Biology and Evolution (2023)

Abstract Future breeding is likely to involve the detection and removal of deleterious alleles, which are mutations that negatively affect crop fitness. However, little is known about the prevalence of such mutations and their effects on phenotypic traits in the context of modern crop breeding. To address this, we examined the number and frequency of deleterious mutations in 350 elite maize inbred lines developed over the past few decades in China and the United States. Our findings reveal an accumulation of weakly deleterious mutations and a decrease in strongly deleterious mutations, indicating the dominant effects of genetic drift and purifying selection for the two types of mutations, respectively. We also discovered that slightly deleterious mutations, when at lower frequencies, were more likely to be heterozygous in the developed hybrids. This is consistent with complementation as a potential explanation for heterosis. Subsequently, we found that deleterious mutations accounted for more of the variation in phenotypic traits than nondeleterious mutations with matched minor allele frequencies, especially for traits related to leaf angle and flowering time. Moreover, we detected fewer deleterious mutations in the promoter and gene body regions of differentially expressed genes across breeding eras than in nondifferentially expressed genes. Overall, our results provide a comprehensive assessment of the prevalence and impact of deleterious mutations in modern maize breeding and establish a useful baseline for future maize improvement efforts.
Changing the Treatment Paradigm for Locally Advanced Rectal Cancer
Authors: Fahima Dossa, Nancy N. Baxter
Journal: New England Journal of Medicine (2023)

The dawn of the "modern" era for the treatment of rectal cancer began with the adoption of total mesorectal excision (TME) — a revolution in surgical care that emphasized the achievement of negative margins through sharp dissection along embryologic planes, resulting in a reduced risk of local recurrence. However, multimodal therapy for locally advanced rectal cancer has remained linked to treatment paradigms of the past. Guidelines for treatment with a combination of chemotherapy and radiotherapy in addition to surgery evolved from recommendations put forth in the early 1990s.1 Although advances in management have occurred, the focus has been largely on . . .
Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells
Authors: Anna Palau, Filip Segerberg, Michael Lidschreiber, Katja Lidschreiber, Aonghus J. Naughton, Maria Needhamsen, Lisa Anna Jung, Maja Jagodic, Patrick Cramer, Sören Lehmann, Mattias Carlsten, Andreas Lennartsson
Journal: Leukemia (2023)

Abstract Isocitrate dehydrogenase (IDH) mutations are found in 20% of acute myeloid leukemia (AML) patients. However, only 30–40% of the patients respond to IDH inhibitors (IDHi). We aimed to identify a molecular vulnerability to tailor novel therapies for AML patients with IDH mutations. We characterized the transcriptional and epigenetic landscape with the IDH2i AG-221, using an IDH2 mutated AML cell line model and AML patient cohorts, and discovered a perturbed transcriptional regulatory network involving myeloid transcription factors that were partly restored after AG-221 treatment. In addition, hypermethylation of the HLA cluster caused a down-regulation of HLA class I genes, triggering an enhanced natural killer (NK) cell activation and an increased susceptibility to NK cell-mediated responses. Finally, analyses of DNA methylation data from IDHi-treated patients showed that non-responders still harbored hypermethylation in HLA class I genes. In conclusion, this study provides new insights suggesting that IDH mutated AML is particularly sensitive to NK cell-based personalized immunotherapy.